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1.
Biomedicines ; 9(8)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34440158

RESUMO

The use of ionizing radiation (IR) during radiotherapy can induce malignant effects, such as metastasis, which contribute to poor prognoses in lung cancer patients. Here, we explored the ability of dendrobine, a plant-derived alkaloid from Dendrobium nobile, to improve the efficacy of radiotherapy in non-small cell lung cancer (NSCLC). We employed Western blotting, quantitative real-time (qRT)-PCR, transwell migration assays, and wound-healing assays to determine the effects of dendrobine on the migration and invasion of A549 lung cancer cells in vitro. Dendrobine (5 mm) inhibited γ-irradiation-induced migration and invasion of A549 cells by suppressing sulfatase2 (SULF2) expression, thus inhibiting IR-induced signaling. To investigate the inhibitory effects of dendrobine in vivo, we established a mouse model of IR-induced metastasis by injecting BALB/c nude mice with γ-irradiated A549 cells via the tail vein. As expected, injection with γ-irradiated cells increased the number of pulmonary metastatic nodules in mice (0 Gy/DPBS, 9.8 ± 1.77; 2 Gy/DPBS, 20.87 ± 1.42), which was significantly reduced with dendrobine treatment (2 Gy/Dendrobine, 10.87 ± 0.71), by prevention of IR-induced signaling. Together, these findings demonstrate that dendrobine exerts inhibitory effects against γ-irradiation-induced invasion and metastasis in NSCLC cells in vitro and in vivo at non cytotoxic concentrations. Thus, dendrobine could serve as a therapeutic enhancer to overcome the malignant effects of radiation therapy in patients with NSCLC.

2.
Plants (Basel) ; 10(8)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34451680

RESUMO

Weigela subsessilis is used in folk medicine to treat pain and allergic syndromes in Korea. However, the antibacterial and anti-inflammatory activities of W. subsessilis callus extract remain unexplored. In this study, we aimed to evaluate the W. subsessilis callus of pharmacological activity. Therefore, we first established in vitro calluses of W.subsessilis via plant tissue culture methods. We then evaluated the antioxidant and anti-inflammatory effects of W. subsessilis callus extract in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells. The W. subsessilis callus extract showed antioxidant and anti-inflammatory effects. These effects were regulated via suppression of mitogen-activated protein kinase signaling through LPS-induced translocation of nuclear factor kappa B (NF-κB) p65 from the cytoplasm to the nucleus. W. subsessilis callus extract also showed antibacterial and anti-inflammatory activities in Propionibacterium acnes-treated HaCaT keratinocyte cells. These results indicate that W. subsessilis callus extract has antioxidant, antibacterial and anti-inflammatory activities, suggesting its possible application in the treatment of inflammatory disorders.

3.
Plants (Basel) ; 10(7)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34371579

RESUMO

The Dendrobium species (Orchidaceae) has been cultivated as an ornamental plant as well as used in traditional medicines. In this study, the chemical profiles of Dendrobii Herba, used as herbal medicine, Dendrobium in two different species, their hybrid, and the gamma-irradiated mutant lines of the hybrid, were systematically investigated via ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QToF MS). Among the numerous peaks detected, 17 peaks were unambiguously identified. Gigantol (1), (1R,2R)-1,7-hydroxy-2,8-methoxy-2,3-dihydrophenanthrene-4(1H)-one (2), tristin (3), (-)-syringaresinol (4), lusianthridin (5), 2,7-dihydroxy-phenanthrene-1,4-dione (6), densiflorol B (7), denthyrsinin (8), moscatilin (9), lusianthridin dimer (10), batatasin III (11), ephemeranthol A (12), thunalbene (13), dehydroorchinol (14), dendrobine (15), shihunine (16), and 1,5,7-trimethoxy-2-phenanthrenol (17), were detected in Dendrobii Herba, while 1, 2, and 16 were detected in D. candidum, 1, 11, and 16 in D. nobile, and 1, 2, and 16 in the hybrid, D. nobile × candidum. The methanol extract taken of them was also examined for cytotoxicity against FaDu human hypopharynx squamous carcinoma cells, where Dendrobii Herba showed the greatest cytotoxicity. In the untargeted metabolite analysis of 436 mutant lines of the hybrid, using UPLC-QToF MS and cytotoxicity measurements combined with multivariate analysis, two tentative flavonoids (M1 and M2) were evaluated as key markers among the analyzed metabolites, contributing to the distinction between active and inactive mutant lines.

4.
Mar Drugs ; 19(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34436304

RESUMO

The epithelial-mesenchymal transition (EMT) of cancer cells is a crucial process in cancer cell metastasis. An Aquimarina sp. MC085 extract was found to inhibit A549 human lung cancer cell invasion, and caprolactin C (1), a new natural product, α-amino-ε-caprolactam linked to 3-methyl butanoic acid, was purified through bioactivity-guided isolation of the extract. Furthermore, its enantiomeric compound, ent-caprolactin C (2), was synthesized. Both 1 and 2 inhibited the invasion and γ-irradiation-induced migration of A549 cells. In transforming growth factor-ß (TGF-ß)-treated A549 cells, 2 inhibited the phosphorylation of Smad2/3 and suppressed the EMT cell marker proteins (N-cadherin, ß-catenin, and vimentin), as well as the related messenger ribonucleic acid expression (N-cadherin, matrix metalloproteinase-9, Snail, and vimentin), while compound 1 did not suppress Smad2/3 phosphorylation and the expression of EMT cell markers. Therefore, compound 2 could be a potential candidate for antimetastatic agent development, because it suppresses TGF-ß-induced EMT.

5.
Molecules ; 26(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921835

RESUMO

Zingiber cassumunar Roxb. (Zingiberaceae), is an important medicinal plant known as "Plai (Phlai)" in Thailand, "Bangle" in Indonesia, and "Bulei" in China. Traditionally, this plant has been used to treat inflammation, pain, and respiratory problems. The rhizomes are the primary part of the plant that has been used for medicinal purposes due to their constituents with therapeutic properties, including phenylbutenoids, curcuminoids, and essential oils. Since the 1970s, many studies have been conducted on the phytochemicals and bioactivities of Z. cassumunar to establish fundamental scientific evidence that supports its use in traditional medicine. The accumulated biological studies on the extracts, solvent fractions, and constituents of Z. cassumunar have described their diverse medicinal properties, including antioxidant, anti-inflammatory, anticancer, neuroprotective/neurotrophic, cosmeceutical, and antifungal/antimicrobial bioactivities. In this review, we summarize information on the phytochemicals of Z. cassumunar and the bioactivities of its extracts and constituents.


Assuntos
Compostos Fitoquímicos/química , Zingiberaceae/química , Animais , Anti-Inflamatórios/química , Antioxidantes/química , Humanos , Óleos Voláteis/química , Extratos Vegetais/química , Plantas Medicinais/química
6.
Plants (Basel) ; 9(12)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33287317

RESUMO

Toona sinensis has been traditionally used to treat dysentery, enteritis, flatulence, and itchiness. However, the existence of anti-inflammatory effects of T. sinensis on Propionibacterium acnes-induced skin disease is unknown. In vitro cultures of plant cells and tissues produced under controlled conditions offer a continuous production platform for plant natural products including pigments and anti-inflammatory agents. In this study, we determine the anti-inflammatory activities of an extract of in vitro grown adventitious shoots of T. sinensis on P. acnes, the etiologic agent of skin inflammation. The extract of T. sinensis showed antioxidant and anti-inflammatory activity in LPS-treated RAW264.7 cells. It also had antibacterial activity and anti-inflammatory effects on P. acnes-treated HaCaT cells. In addition, these effects were regulated by suppression of the mitogen-activated protein kinase (MAPK) pathways. These results suggesting the potential application of adventitious shoots of T. sinensis grown with an in vitro proliferation system as a medicine for treating P. acnes-induced inflammatory skin disease.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33029164

RESUMO

Radiotherapy using ionizing radiation is a major therapeutic modality for advanced human lung cancers. However, ionizing radiation itself can induce malignant behaviors such as cancer cell migration and invasion, leading to local recurrence or distal metastasis. Therefore, safer and more effective agents that inhibit the metastatic behaviors of cancer cells in radiotherapy are needed. As a part of our ongoing search for new radiotherapy enhancers from medicinal herbs, we isolated the following triterpenoids from the ethanol extract of Centella asiatica: asiatic acid (1), madecassic acid (2), and asiaticoside (3). These compounds inhibited the ionizing radiation-induced migration and invasion of A549 human lung cancer cells at noncytotoxic concentrations. These results suggest that triterpenoids 1-3 isolated from C. asiatica are candidate natural compounds to enhance the effect of radiotherapy in patients with non-small-cell lung cancer.

8.
Sci Rep ; 10(1): 3652, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32107458

RESUMO

In this study we assessed the clinical significance of an epithelial-mesenchymal transition (EMT) gene signature and explored its association with the tumor microenvironment related to immunotherapy in patients with head and neck squamous cell carcinoma (HNSCC). Genes were selected when mRNA levels were positively or negatively correlated with at least one well-known EMT marker. We developed an EMT gene signature consisting of 82 genes. The patients were classified into epithelial or mesenchymal subgroups according to EMT signature. The clinical significance of the EMT signature was validated in three independent cohorts and its association with several immunotherapy-related signatures was investigated. The mesenchymal subgroup showed worse prognosis than the epithelial subgroup, and significantly elevated PD-1, PD-L1, and CTLA-4 levels, and increased interferon-gamma, cytolytic, T cell infiltration, overall immune infiltration, and immune signature scores. The relationship between PD-L1 expression and EMT status in HNSCC after treatment with TGF-ß was validated in vitro. In conclusion, the EMT gene signature was associated with prognosis in HNSCC. Additionally, our results suggest that EMT is related to immune activity of the tumor microenvironment with elevated immune checkpoint molecules.


Assuntos
Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas de Neoplasias/biossíntese , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Microambiente Tumoral , Idoso , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Transcriptoma
9.
Molecules ; 25(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085431

RESUMO

Dendrobii Herba is an herbal medicine that uses the stems of Dendrobium species (Orchidacea). It has been traditionally used to treat fever, hydrodipsomania, stomach disorders, and amyotrophia. In our previous study, a bibenzyl compound, moscatilin, which is isolated from Dendrobii Herba, showed potent cytotoxicity against a FaDu human pharyngeal squamous carcinoma cell line. Prompted by this finding, we performed additional studies in FaDu cells to investigate the mechanism of action. Moscatilin induced FaDu cell death by using 5 µM of concentration and by mediating apoptosis, whereas cell proliferation following treatment with 1 µM of moscatilin was not suppressed to the same levels as by the anti-cancer agent, cisplatin. Apoptosis-related protein expression (cleaved caspase-8, cleaved caspase-7, cytochrome c, cleaved caspase-9, cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP) was increased by treating with 5 µM of moscatilin. This suggests that moscatilin-mediated apoptosis is associated with the extrinsic and intrinsic apoptotic signaling pathways. In addition, moscatilin-induced apoptosis was mediated by the c-Jun N-terminal kinase (JNK) signaling pathway. Overall, this study identified additional biological activity of moscatilin derived from natural products and suggested its potential application as a chemotherapeutic agent for the management of head and neck squamous cell carcinoma.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Benzil/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
10.
Molecules ; 24(12)2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242649

RESUMO

Two new phenanthrenes, (1R,2R)-1,7-hydroxy-2,8-methoxy-2,3-dihydrophenanthrene-4(1H)-one (1) and 2,7-dihydroxy-phenanthrene-1,4-dione (2), were isolated from the ethyl acetate-soluble fraction of Dendrobii Herba, together with seven known phenanthrenes (3-9), two bibenzyls (10-12), and a lignan (13). Structures of 1 and 2 were elucidated by analyzing one-dimensional (1D) and two-dimensional (2D)-NMR and High-resolution electrospray ionization mass spectra (HR-ESI-MS) data. The absolute configuration of compound 1 was confirmed by the circular dichroism (CD) spectroscopic method. In cytotoxicity assay using FaDu human hypopharynx squamous carcinoma cell line, compounds 3-6, 8, 10, and 12 showed activities, with IC50 values that ranged from 2.55 to 17.70 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Orchidaceae/química , Fenantrenos/farmacologia , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Carcinoma de Células Escamosas , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Hipofaríngeas , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fenantrenos/química , Extratos Vegetais/química , Relação Estrutura-Atividade
11.
Exp Mol Med ; 51(2): 1-10, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755594

RESUMO

Sublethal doses of γ-rays promote cancer cell invasion by stimulating a signaling pathway that sequentially involves p53, sulfatase 2 (SULF2), ß-catenin, interleukin-6 (IL-6), signal transducer and activator of transcription 3 (STAT3), and Bcl-XL. Given that Bcl-XL can increase O2•- production by stimulating respiratory complex I, the possible role of mitochondrial reactive oxygen species (ROS) in γ-irradiation-induced cell invasion was investigated. Indeed, γ-irradiation promoted cell invasion by increasing mitochondrial ROS levels, which was prevented by metformin, an inhibitor of complex I. γ-Irradiation-stimulated STAT3 increased the expression of superoxide dismutase 2 (SOD2), a mitochondrial enzyme that catalyzes the conversion of O2•- to hydrogen peroxide (H2O2). In contrast to O2•-, H2O2 functions as a signaling molecule. γ-Irradiation consistently stimulated the Src-dependent invasion pathway in a manner dependent on both complex I and SOD2. SOD2 was also essential for the invasion of un-irradiated cancer cells induced by upregulation of Bcl-XL, an intracellular oncogene, or extracellular factors, such as SULF2 and IL-6. Overall, these data suggested that SOD2 is critical for the malignant effects of radiotherapy and tumor progression through diverse endogenous factors.


Assuntos
Raios gama , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Superóxido Dismutase/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Movimento Celular/genética , Expressão Gênica , Humanos , Interleucina-6/metabolismo , Mitocôndrias/genética , Estresse Oxidativo , Fosforilação , Tolerância a Radiação/genética , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/genética , Quinases da Família src/genética , Quinases da Família src/metabolismo
12.
G3 (Bethesda) ; 9(3): 921-931, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30670610

RESUMO

Rho GTPases play critical roles in cell proliferation and cell death in many species. As in animal cells, cells of the budding yeast Saccharomyces cerevisiae undergo regulated cell death under various physiological conditions and upon exposure to external stress. The Rho5 GTPase is necessary for oxidant-induced cell death, and cells expressing a constitutively active GTP-locked Rho5 are hypersensitive to oxidants. Yet how Rho5 regulates yeast cell death has been poorly understood. To identify genes that are involved in the Rho5-mediated cell death program, we performed two complementary genome-wide screens: one screen for oxidant-resistant deletion mutants and another screen for Rho5-associated proteins. Functional enrichment and interaction network analysis revealed enrichment for genes in pathways related to metabolism, transport, and plasma membrane organization. In particular, we find that ATG21, which is known to be involved in the CVT (Cytoplasm-to-Vacuole Targeting) pathway and mitophagy, is necessary for cell death induced by oxidants. Cells lacking Atg21 exhibit little cell death upon exposure to oxidants even when the GTP-locked Rho5 is expressed. Moreover, Atg21 interacts with Rho5 preferentially in its GTP-bound state, suggesting that Atg21 is a downstream target of Rho5 in oxidant-induced cell death. Given the high degree of conservation of Rho GTPases and autophagy from yeast to human, this study may provide insight into regulated cell death in eukaryotes in general.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Morte Celular , Endopeptidases/metabolismo , Estresse Oxidativo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo , Oxidantes/toxicidade , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/fisiologia
13.
Nat Prod Res ; 33(24): 3582-3586, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29897257

RESUMO

Radiotherapy is routinely used in the treatment of lung cancer patients. However, it often causes malignant effects, such as promoting cancer cell migration and invasion. Previous studies demonstrated that ionizing radiation (IR) promotes cancer cell invasion by stimulating the ß-catenin, IL-6, STAT3, and Bcl-XL signaling pathway or the PI3K, Akt, and NF-κB signaling pathway. Both Bcl-XL and NF-κB stimulate the secretion of matrix metalloproteases (MMPs), including MMP-2 and MMP-9. In the present study, linarin isolated from Chrysanthemum morifolium flowers significantly decreased the IR-induced cell migration and invasion at a concentration of 5 µM in A549 cells. This effect was mediated via MMP-9 downregulation and the suppression of NF-κB activation by inhibiting NF-κB and IκB-α phosphorylation. However, linarin did not affect the STAT3/Bcl-XL pathway or the stabilization of ß-catenin. Overall, these results suggest that linarin repressed the MMP-9-dependent invasion pathway by regulating NF-κB activity, thereby inhibiting IR-induced cancer metastasis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Movimento Celular , Regulação para Baixo/efeitos dos fármacos , Glicosídeos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Induzidas por Radiação/prevenção & controle , Células A549 , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/efeitos dos fármacos , Chrysanthemum/química , Glicosídeos/isolamento & purificação , Glicosídeos/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Invasividade Neoplásica/prevenção & controle , Fosforilação/efeitos dos fármacos
14.
Cancer Lett ; 424: 127-135, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29596889

RESUMO

The plasticity of solid tumors between the epithelial and mesenchymal states critically influences their malignant progression and metastasis. The epithelial-mesenchymal transition (EMT), which supports cancer cell invasion and metastasis, is promoted by pro-survival members (e.g., Bcl-2 and Bcl-XL) of the Bcl-2 protein family, which are well-known key apoptosis regulators. We found that Bcl-w, another pro-survival member, promotes EMT by increasing respiratory complex-I activity and reactive oxygen species (ROS) levels. In contrast, pro-apoptotic Bax facilitates mesenchymal-epithelial transition by binding to complex-I, which inhibits complex-I-induced ROS production. Functional antagonism between pro-survival and pro-apoptotic proteins in regulating tumor plasticity was directly confirmed by co-expressing Bax with Bcl-w or Bcl-XL. Therefore, the balance between the functionally opposing Bcl-2 proteins appears to be a critical determinant of cancer cell phenotypes. We further showed that sub-lethal doses of γ-radiation induced EMT by increasing Bcl-XL and Bcl-w levels and complex-I activity. We propose that Bcl-2 proteins and complex-I are potential targets for preventing tumor progression and the malignant actions of radiotherapy.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias da Mama/patologia , Complexo I de Transporte de Elétrons/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Plasticidade Celular , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Camundongos , Transplante de Neoplasias , Espécies Reativas de Oxigênio/metabolismo
15.
Cancer Res ; 77(11): 3092-3100, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28377455

RESUMO

The tumor suppressor p53 binds prosurvival Bcl-2 family proteins such as Bcl-w and Bcl-XL to liberate Bax, which in turn exerts proapoptotic or anti-invasive functions depending on stress context. On the basis of our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here, we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-XL also served as a target of the cooperative action of p53 and p21. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Cancer Res; 77(11); 3092-100. ©2017 AACR.


Assuntos
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Transfecção
16.
Oncotarget ; 7(13): 16090-103, 2016 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-26895473

RESUMO

Cancer cells that survive radiotherapy often display enhanced invasiveness and resistance to death stimuli. Previous findings have suggested that ionizing radiation (IR) induces such undesirable effects by stimulating the STAT3/Bcl-XL pathway. To identify novel cellular components that mediate these actions of IR, we irradiated lung cancer cells with sublethal doses of y-rays and screened for the induction of IR-responsive genes by microarray analysis. The genes encoding 2 extracellular proteins, SULF2 and IL-6, were found to be upregulated, and these results were confirmed by polymerase chain reactions and western blot analyses. Because the IR-mediated induction of SULF2 was a novel finding, we also confirmed the phenomenon in vivo using xenograft tumors in mice. Analyses of signaling processes revealed that IR induced SULF2 expression via p53, which then promoted IL-6 expression by stabilizing ß-catenin, followed by stimulation of the STAT3/Bcl-XL pathway. Consistently, both SULF2 and IL-6 mediated IR-induced invasion and resistance to death stimuli. To investigate whether SULF2 contributes to IR-induced tumor metastasis, we irradiated tumors in mice with sublethal doses of IR. This treatment promoted the entry of tumor cells into the blood stream (intravasation), which was abolished by downregulating SULF2 expression in tumor cells. These results demonstrated that SULF2 can mediate the detrimental effects of IR in vivo. Therefore, SULF2 may be potentially used as a therapeutic and diagnostic target to predict and overcome the malignant effects of IR, particularly in tumors expressing p53 wild-type.


Assuntos
Interleucina-6/biossíntese , Neoplasias Pulmonares/patologia , Tolerância a Radiação/fisiologia , Sulfotransferases/metabolismo , Animais , Linhagem Celular Tumoral , Raios gama , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia , Sulfatases , Sulfotransferases/efeitos da radiação
17.
Int J Oncol ; 47(4): 1257-65, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26314270

RESUMO

We previously reported that podophyllotoxin acetate (PA) radiosensitizes NCI-H460 cells. Here, we confirmed that PA treatment also induces cell death among two other non-small cell lung cancer (NSCLC) cell lines: NCI-H1299 and A549 cells (IC50 values = 7.6 and 16.1 nM, respectively). Our experiments further showed that PA treatment was able to induce cell death via various mechanisms. First, PA dose-dependently induced cell cycle arrest at G2/M phase, as shown by accumulation of the mitosis-related proteins, p21, survivin and Aurora B. This G2/M phase arrest was due to the PA-induced inhibition of microtubule polymerization. Together, the decreased microtubule polymerization and increased cell cycle arrest induced DNA damage (reflected by accumulation of γ-H2AX) and triggered the induction of intrinsic and extrinsic apoptotic pathways, as shown by the time-dependent activations of caspase-3, -8 and -9. Second, PA time-dependently activated the pro-apoptotic ER stress pathway, as evidenced by increased expression levels of BiP, CHOP, IRE1-α, phospho-PERK, and phospho-JNK. Third, PA activated autophagy, as reflected by time-dependent increases in the expression levels of beclin-1, Atg3, Atg5 and Atg7, and the cleavage of LC3. Collectively, these results suggest a model wherein PA decreases microtubule polymerization and increases cell cycle arrest, thereby inducing apoptotic cell death via the activation of DNA damage, ER stress and autophagy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Podofilotoxina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Immunoblotting , Imuno-Histoquímica , Microtúbulos/efeitos dos fármacos
18.
Biochem Biophys Res Commun ; 445(1): 191-5, 2014 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-24502947

RESUMO

The human Z-type α1-antitrypsin variant has a strong tendency to accumulate folding intermediates due to extremely slow protein folding within the endoplasmic reticulum (ER) of hepatocytes. Human α1-antitrypsin has 17 peptidyl-prolyl bonds per molecule; thus, the effect of peptidyl-prolyl isomerases on Z-type α1-antitrypsin protein folding was analyzed in this study. The protein level of Cpr2p, a yeast ER peptidyl-prolyl isomerase, increased more than two-fold in Z-type α1-antitrypsin-expressing yeast cells compared to that in wild-type α1-antitrypsin-expressing cells. When CPR2 was deleted from the yeast genome, the cytotoxicity of Z-type α1-antitrypsin increased significantly. The interaction between Z-type α1-antitrypsin and Cpr2p was confirmed by co-immunoprecipitation. In vitro folding assays showed that Cpr2p facilitated Z-type α1-antitrypsin folding into the native state. Furthermore, Cpr2p overexpression significantly increased the extracellular secretion of Z-type α1-antitrypsin. Our results indicate that ER peptidyl-prolyl isomerases may rescue Z-type α1-antitrypsin molecules from retarded folding and eventually relieve clinical symptoms caused by this pathological α1-antitrypsin.


Assuntos
Peptidilprolil Isomerase/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , alfa 1-Antitripsina/metabolismo , Retículo Endoplasmático/enzimologia , Regulação da Expressão Gênica , Teste de Complementação Genética , Variação Genética , Humanos , Immunoblotting , Imunoprecipitação , Mutação , Peptidilprolil Isomerase/química , Peptidilprolil Isomerase/genética , Ligação Proteica , Dobramento de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , alfa 1-Antitripsina/química , alfa 1-Antitripsina/genética
19.
Oncol Rep ; 29(6): 2109-13, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23563360

RESUMO

Bmal1 is a core factor in the regulation of circadian rhythms. Previous studies have shown that Bmal1 suppresses tumor growth in cell culture and animal models and is downregulated in certain types of cancer. The aim of the present study was to investigated whether Bmal1 influences the invasiveness of cancer cells. We demonstrated that knockdown of Bmal1 by RNA interference promoted cancer cell invasion, whereas its overexpression reduced cellular invasiveness. These effects were observed in lung cancer and glioma cells, and occurred regardless of p53 status. Therefore, it appears that Bmal1 suppresses the invasion of multiple cancer types in a p53-independent manner. Bmal1 knockdown-induced cancer cell invasion was accompanied by activation of the PI3K-Akt-MMP-2 pathway, and was prevented by inhibitors of PI3K, Akt or MMP-2. This suggests that Bmal1 suppresses cell invasion by blocking the PI3K-Akt-MMP-2 pathway. Since this invasion pathway is activated by the oncogene Bcl-w, we investigated whether Bmal1 affects the activity of Bcl-w. As expected, Bmal1 attenuated the ability of Bcl-w to promote MMP-2 accumulation and cell invasion, supporting the idea that Bmal1 antagonizes Bcl-w activity. Collectively, our data suggest that Bmal1 is a tumor suppressor, capable of suppressing cancer cell growth and invasiveness, and support the recent proposal that there is a tight molecular link between circadian rhythms and tumor formation/progression.


Assuntos
Fatores de Transcrição ARNTL/fisiologia , Movimento Celular , Metaloproteinase 2 da Matriz/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Genes Supressores de Tumor , Humanos , Invasividade Neoplásica , RNA Interferente Pequeno/genética
20.
Cancer Lett ; 335(2): 270-7, 2013 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-23438693

RESUMO

Mdm2 is an oncoprotein that induces the degradation of the tumor suppressor, p53. Here, we show that Mdm2 increases the mRNA levels of Slug by binding to and stabilizing the Slug mRNA. While this effect of Mdm2 was observed in both p53-null and p53-expressing cancer cells, it increased the protein levels of Slug only in the former cells. Mdm2 consistently induced Slug-dependent events, such as decreases in E-cadherin levels and increases in cellular invasiveness, only in p53-null cells. Therefore, the binding of Mdm2 to the Slug mRNA appears to provide a novel mechanism through which Mdm2 promotes tumor progression in a manner independent of the presence of p53.


Assuntos
Neoplasias do Colo/patologia , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Invasividade Neoplásica , Fatores de Transcrição da Família Snail , Proteína Supressora de Tumor p53
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